Iron Sucrose, which belongs to the therapeutic class of haemitinic is a complex of polynuclear iron (III) hydroxide in sucrose having molecular weight approximately between 34,000 and 60,000 daltons, and structural formula [Na2Fe5O8(OH).3(H2O)]n.m(C12H22O11), where n is the degree of polymerization and m is the number of sucrose molecules associated with the iron(III) hydroxide.
Iron sucrose containing 30% sucrose (w/v) is an injectable, which is administered intravenously for replenishing body iron stores in patients with iron deficiency on chronic hemodialysis and receiving erythropoietin.
There are numerous references in prior art, which disclose methods for preparation of complexes of carbohydrates with various metals.
U.S. Pat. No. 4,746,730 (assigned to Medinianum Farmaceutci) discloses a method for preparation of complexes of iron and various carbohydrates like fructose and saccharose. The method comprises addition of an aqueous solution of ferric chloride to a fructose solution followed by addition of aqueous potassium hydroxide solution to get pH between 7.8 and 8.5. The complex is obtained by a process of lyophilisation which is very expensive on an industrial scale.
U.S. Pat. No. 4,994,283 (assigned to Procter and Gamble) discloses a method for preparing iron-sugar carbohydrate complex, which comprises initial preparation of a complex of calcium and a sugar followed by preparation of the iron-sugar complex by reaction with an iron source such as ferrous ammonium sulfate and treating the resultant iron-sugar complex with malic acid to give the desired iron-sugar complex.
The method is quite lengthy as it does not involve the direct preparation of the iron-sugar complex and rather involves the intermediary of a calcium-sugar complex from which the product is obtained. Further, there is no surety that the iron-sugar complex obtained will be free from the calcium-sugar complex.
CA 1 253 821 (assigned to Pfeifer & Langer) discloses a method for preparation of water soluble iron dextran complex comprising formation of dextran utilizing enzyme and bacteria and subsequently reacting the same with freshly prepared iron (III) hydroxide. The preparation of iron dextran utilizing enzyme and bacteria is very selective and not convenient for commercial production.
US 2003/0216566A1 (assigned to Patel, et. al) discloses a method for preparation of a complex of sodium ferric gluconate in sucrose comprising reaction of sodium gluconate with ferric oxyhydroxide to give sodium ferric gluconate which is freeze-dried. The complex thus obtained is added to sucrose solution to give sodium ferric gluconate in sucrose. Also, the choice of the base selection is critical in the process.
IN 187116 (assigned to Alkem Laboratories) teaches a method for preparing saccharated iron oxide by reaction of a ferric salt with an aqueous solution of an inorganic base to give ferric oxyhydroxide which on further treatment with sucrose at pH 6.5 to 7.5 gives saccharin iron oxide.
Although, it is mentioned in IN 187116 that saccharin iron oxide is obtained at pH 6.5 to 7.5 but it is our finding that preparation of saccharin iron oxide at pH 6.5 to 7.5 fails as there is no formation of saccharin iron oxide at the said pH.
WO 2005/094202 A2 (assigned to Navinta LLC) discloses another method for the preparation of Iron sucrose comprising of addition of an inorganic base in a phased manner to an aqueous solution of ferric salts to obtain ferric hydroxide followed by addition to an aqueous solution of sucrose and heating at a temperature of 100-105° C., followed by freeze drying of the resulting product. The iron sucrose thus obtained has to be purified to obtain the product conforming to desired specifications.
The method disclosed in this patent application utilizes freeze drying for isolating iron sucrose, which is however not suitable for industrial purpose, since the isolation method is very expensive.
WO 2005/000210 A2 discloses a general method for the preparation of iron-saccharidic complexes, including iron sucrose. The preparation of iron sucrose disclosed in this patent application involves mixing of the aqueous solution of the ferric salt and sucrose followed by addition of sodium hydroxide solution to give ferric hydroxide sucrose complex. This method has the disadvantage of the inability to monitor whether the ferric salt initially added has been completely converted to ferric hydroxide for further reaction with sucrose solution. Therefore, there is every possibility of the iron sucrose thus formed being contaminated with the ferric salts employed initially and secondly, due to the possible incomplete formation of ferric hydroxide, the yield of iron sucrose will be lower, rendering the process unsuitable for industrial applications. Further, iron sucrose thus obtained has a molecular weight around 1,570,000 daltons (Example 2), which does not conform to the specification for molecular weight desired by the regulatory authorities (34,000 to 60,000 daltons) for Iron sucrose.
Thus the prior art methods have several shortcomings such as                i) utilization of freeze drying, which is expensive on industrial scale,        ii) in one of the prior art methods iron sugar complex is prepared through the intermediary of the calcium complex of the carbohydrate, which is lengthy and more expensive.        iii) glucose is required in conjunction with sucrose for preparation of the iron sucrose complex. Utilization of another carbohydrate like glucose makes the process more costly.        iv) selection of an inorganic base for preparation of ferric oxyhydroxide is critical as inorganic bases like ammonium hydroxide or sodium hydroxide utilized for preparation of ferric oxyhydroxide fails to give the sodium ferric gluconate complex with sodium gluconate.        
There is ample information about the iron complexes in the literature, however for the preparation of iron sucrose the information available is scanty.
Therefore, in view of these shortcomings there is a need for an improved method, which is not only economical and cost-effective but is also simple and overcomes the drawbacks of prior art methods to give iron sucrose complex conforming to regulatory standards.
The present inventors have a simple cost-effective method for preparation of iron-sucrose complex, which comprises reaction of a ferric salt solution with an aqueous solution of an inorganic base at pH between 3.5 and 7.0 to give ferric oxyhydroxide, which is then treated with sucrose solution at a temperature of 20-100° C. and pH 8.0 to 13.0 to give iron-sucrose complex conforming to regulatory specifications.